HIERARCHICAL AND REDUNDANT LYMPHOCYTE SUBSET CONTROL PRECLUDES CYTOMEGALOVIRUS REPLICATION DURING LATENT INFECTION

Reactivation from latent cytomegalovirus (CMV) infection is often asso ciated with conditions of immunosuppression and can result in fatal di sease. Whether the maintenance of systemic CMV latency is mainly gover ned by factors of the infected cell or by immune control functions is unknown. Likewise, the putative immune control mechanisms which could prevent the induction and spread of recurrent CMV infection are not cl early identified. We took advantage of latently infected B cell-defici ent mice and a sensitive method for virus detection to study CMV react ivation after ablation of lymphocyte subsets. A crucial role of both T lymphocytes and natural killer (NK) cells was demonstrated. Within 5 d after depletion of lymphocytes, productive infection occurred in 50% of mice, and 14 d later 100% of mice exhibited recurrent infection. A hierarchy of immune control functions of CD8(+), NK, and CD4(+) cells was established. Reactivation was rare if only one of the lymphocyte subsets was depleted, but was evident after removal of a further subse t, indicating a functional redundancy of control mechanisms. The saliv ary glands were identified as the site of most rapid virus shedding, f ollowed by the detection of recurrent virus in the lungs, and eventual ly in the spleen. Our findings document a previously unknown propensit y of latent CMV genomes to enter productive infection immediately and with a high frequency after immune cell depletion. The data indicate t hat only the sustained cellular immune control prevents CMV replicatio n and restricts the viral genome to a systemic state of latency.